Metastasis, the spread and re-establish of malignant cells from the primary tumor to distant organs, is the most serious problem in the clinical management of cancer. Future strategies for the prevention and control of metastasis must confront the now established fact that cells within the tumor are not identical or static, but are capable of continual change and differ widely in their metastatic potential. A minority of cells within the tumor population (metastatic tumor cell variants) possess greatly exaggerated potential for metastatic spread. The overall goal of the studies outlined in this proposal is to further characterize the induction, regulation and spread of metastatic tumor cell variants within developing tumors and metastases. These studies are now possible through the development of specific monoclonal antibodies which can distinguish metastatic tumor cell variants from their non-metastasizing tumor cell counterparts. This capability presents a unique opportunity to directly monitor, isolate and characterize metastatic variants in their natural setting within the primary tumor and its metastases. Specific goals of these studies are 1) to determine when and where metastatic tumor cell variants arise in primary tumors, and why metastatic variants localize around the tumor vasculature and advancing tumor fronts, 2) to examine the immunological mechanisms and consequences of the tumor-host system which favor the outgrowth and spread of metastatic tumor cell variants and 3) to use recombinant DNA technology to deduce the primary structure of metastasis-associated antigens in experimental mice and human tumors, and examine the regulatory mechanisms involved in their expression. Other long term objects of these studies are to use these and other monoclonal antibodies to rapidly screen environmental and therapeutic conditions which prevent, initiate or accelerate metastatic variant formation.